Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual‐Acting Angiotensin Receptor—Neprilysin Inhibitor (ARNi)

Abstract

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

“…Consistent with its mechanism of action, sacubitril/valsartan administration increased urine cGMP levels following single and multiple‐dose administration, as reported in earlier studies 2, 21. However, urinary cGMP levels remained unchanged following sildenafil single‐dose administration.…”

“…Sacubitril/valsartan exerts its effects by inhibiting neprilysin and blocking the angiotensin II receptor 1 2, 3. Neprilysin inhibition results in increased cGMP, the second‐messenger involved in mediating natriuresis, diuresis, vasodilation, and multiple other beneficial effects of the neprilysin substrates ANP, B‐type natriuretic peptide (BNP), and C‐type natriuretic peptide (CNP) 3.…”

“…A validated liquid chromatography, tandem mass spectroscopy (LC‐MS/MS) method was used for quantification of sildenafil, N‐desmethyl‐sildenafil, and sacubitril/valsartan analytes in plasma 1, 36. The lower limit of quantification values were 1.00 ng/mL for sildenafil, N‐desmethyl‐sildenafil, and sacubitril; 20.0 ng/mL for sacubitrilat; and 10.0 ng/mL for valsartan 2, 16…”

“…cGMP and ANP were measured at SGS Cephac (Saint‐Benoit, France) by radioimmunoassay using commercial kits from Amersham International (Amerhsam, UK) and Izotop (Budapest, Hungary), respectively 2. Urine creatinine was analyzed at Clinical Reference Laboratory (CRL, Cambridgeshire, UK).…”

“…Sacubitril/valsartan is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with heart failure (NYHA Class II–IV) and reduced ejection fraction 1. Following oral administration, sacubitril/valsartan provides exposure to sacubitril, a prodrug which is further metabolized to the active neprilysin inhibitor sacubitrilat (LBQ657), and valsartan, an angiotensin receptor blocker (ARB) 2, 3. Neprilysin inhibition by sacubitrilat increases natriuretic peptide (NP) levels, thereby promoting natriuresis, diuresis, vasodilation, and inhibition of maladaptive fibrotic remodeling via their second‐messenger cyclic guanosine monophosphate (cGMP) 3, 4.…”